2. Academic Validation
  3. Molecular editing of NSC-666719 enabling discovery of benzodithiazinedioxide-guanidines as anticancer agents

Molecular editing of NSC-666719 enabling discovery of benzodithiazinedioxide-guanidines as anticancer agents

  • RSC Med Chem. 2024 Jan 30;15(3):937-962. doi: 10.1039/d3md00648d.
Vajja Krishna Rao 1,  Subarno Paul 2,  Mitchell Gulkis 3,  Zhihang Shen 4,  Haritha Nair 5,  Amandeep Singh 6,  Chenglong Li 4,  Arun K Sharma 6,  Melike Çağlayan 3,  Chinmay Das 2,  Biswajit Das 2,  Chanakya N Kundu 2,  Satya Narayan 5,  Sankar K Guchhait 1
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER) Sector 67, SAS Nagar Mohali Punjab 160062 India [email protected].
  • 2 Cancer Biology Division, School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Deemed to be University Campus-11, Patia Bhubaneswar-751024 Odisha India [email protected].
  • 3 Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida 1200 Newell Drive Gainesville FL 32610 USA.
  • 4 Department of Medicinal Chemistry, College of Pharmacy, University of Florida 1345 Center Drive Gainesville FL 32610 USA.
  • 5 Department of Anatomy and Cell Biology, College of Medicine, University of Florida 1200 Newell Drive Gainesville FL 32610 USA [email protected].
  • 6 Department of Pharmacology, Penn State Cancer Institute, CH72, Penn State College of Medicine 500 University Drive Hershey PA 17033 USA.
PMID: 38516586 DOI: 10.1039/d3md00648d
Abstract

DNA Polymerase β (Polβ) is crucial for the base excision repair (BER) pathway of DNA damage repair and is an attractive target for suppressing tumorigenesis as well as chemotherapeutic intervention of Cancer. In this study, a unique strategy of scaffold-hopping-based molecular editing of a bioactive agent NSC-666719 was investigated, which led to the development of new molecular motifs with Polβ inhibitory activity. NSC compound and its analogs (two series) were prepared, focusing on pharmacophore-based molecular diversity. Most compounds showed higher activities than the parent NSC-666719 and exhibited effects on Apoptosis. The inhibitory activity of Polβ was evaluated in both in vitro reconstituted and in vivo intact cell systems. Compound 10e demonstrated significant Polβ interaction and inhibition characteristics, including direct, non-covalent, reversible, and comparable binding affinity. The investigated approach is useful, and the discovered novel analogs have a high potential for developing as Anticancer therapeutics.

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